Bottom Line:
In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis.Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis.Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD.

ABSTRACTDiabesity-associated metabolic stresses modulate the development of Alzheimer's disease (AD). For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ) in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum β-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD.

pone.0134531.g004: Serum Aβ40 and Aβ42 quantification.The levels of (A) Serum Aβ40 and (B) Serum Aβ42 of NCD and HFSTZ AD mice were measured after 11weeks of dietary manipulations by ELISA. Bars represent the mean ± SEM of at least three independent experiments. Significant differences (p < 0.001, unpaired t-tests) among the groups are labeled as ***.

Mentions:
Serum Aβ levels were higher in HFSTZ AD mice and were associated with the extent of hepatic steatosis, obesity, and elevated blood glucose. A previous study suggested that the serum level of Aβ in AD mice increases with elevated glucose intolerance and insulin resistance [16]. To assess whether hyperglycemia and hyperinsulinemia in HFSTZ AD mice correlated with serum Aβ, serum levels of Aβ40 (Fig 4A) and Aβ42 (Fig 4B) were measured. Both of them were significantly increased in AD mice after 11 weeks of HFSTZ treatment. Furthermore, the mean serum Aβ40 concentration in NCD AD mice was 10-fold higher than that of Aβ42. However, there was only a 5-fold difference between Aβ40 and Aβ42 in HFSTZ AD mice. The potential correlations between serum Aβ and weight gain, blood glucose, leptin, and hepatic TG from the data pool of AD mice under NCD and HFSTZ conditions were assessed by Pearson’s correlation analysis. As shown in Table 1, serum Aβ40 and Aβ42 levels were moderately correlated (R = 0.751). Both serum Aβ40 and Aβ42 levels were moderately correlated with body weight gain (R = 0.578 for Aβ40 and 0.727 for Aβ42) and blood glucose (R = 0.629 for Aβ40, 0.599 for Aβ42), and weakly correlated with leptin (R = 0.457 for Aβ40 and 0.445 for Aβ42). On the other hand, serum Aβ40 and Aβ42 levels were moderately and weakly correlated with hepatic TG, respectively (R = 0.511 for Aβ40 and 0.490 for Aβ42). However, serum Aβ40 and Aβ42 levels were not correlated with serum TG. Consistently, weight gain, blood glucose, leptin, and epididymal fat weight (% of body weight) were more correlated with hepatic TG than serum TG.

pone.0134531.g004: Serum Aβ40 and Aβ42 quantification.The levels of (A) Serum Aβ40 and (B) Serum Aβ42 of NCD and HFSTZ AD mice were measured after 11weeks of dietary manipulations by ELISA. Bars represent the mean ± SEM of at least three independent experiments. Significant differences (p < 0.001, unpaired t-tests) among the groups are labeled as ***.

Mentions:
Serum Aβ levels were higher in HFSTZ AD mice and were associated with the extent of hepatic steatosis, obesity, and elevated blood glucose. A previous study suggested that the serum level of Aβ in AD mice increases with elevated glucose intolerance and insulin resistance [16]. To assess whether hyperglycemia and hyperinsulinemia in HFSTZ AD mice correlated with serum Aβ, serum levels of Aβ40 (Fig 4A) and Aβ42 (Fig 4B) were measured. Both of them were significantly increased in AD mice after 11 weeks of HFSTZ treatment. Furthermore, the mean serum Aβ40 concentration in NCD AD mice was 10-fold higher than that of Aβ42. However, there was only a 5-fold difference between Aβ40 and Aβ42 in HFSTZ AD mice. The potential correlations between serum Aβ and weight gain, blood glucose, leptin, and hepatic TG from the data pool of AD mice under NCD and HFSTZ conditions were assessed by Pearson’s correlation analysis. As shown in Table 1, serum Aβ40 and Aβ42 levels were moderately correlated (R = 0.751). Both serum Aβ40 and Aβ42 levels were moderately correlated with body weight gain (R = 0.578 for Aβ40 and 0.727 for Aβ42) and blood glucose (R = 0.629 for Aβ40, 0.599 for Aβ42), and weakly correlated with leptin (R = 0.457 for Aβ40 and 0.445 for Aβ42). On the other hand, serum Aβ40 and Aβ42 levels were moderately and weakly correlated with hepatic TG, respectively (R = 0.511 for Aβ40 and 0.490 for Aβ42). However, serum Aβ40 and Aβ42 levels were not correlated with serum TG. Consistently, weight gain, blood glucose, leptin, and epididymal fat weight (% of body weight) were more correlated with hepatic TG than serum TG.

Bottom Line:
In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis.Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis.Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD.

ABSTRACTDiabesity-associated metabolic stresses modulate the development of Alzheimer's disease (AD). For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ) in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum β-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD.